Tricyclic heterocyclic sulfonamide and sulfonic ester derivatives

ABSTRACT

Novel tricyclic heterocyclic sulfonamide derivatives and sulfonic ester derivatives which have each an antitumor action and are represented by the following general formula (I) and processes for producing the same are provided. These compounds have each an excellent antitumor activity. 
     A sulfonamide derivative or a sulfonic ester derivative represented by the following general formula (I): ##STR1## {G represents an aromatic 5- or 6-membered ring; L represents 0 or --N(R 1 )-- (R 1  represents hydrogen or lower alky); and M represents a tricyclic structure selected from among the following ones; ##STR2##  rings A and B represent each an unsaturated 5- or 6-membered ring; X represents N(R 2 ), (wherein R 2  represents hydrogen or lower alkyl), or NHCO; 
     Y represents O, S(O) n , C(R 3 )(R 4 ), C(O), N(R 5 ), CH(R 6 )CH(R 7 ), C(R 8 )═C(R 9 ), N(R 10 )C(O), N═C(R 11 ), OCH(R 12 ), S(O) n  CH(R 13 ) or N(R 14 )CH(R 15 ); 
     Z represents nitrogen or C(R 16 ) 
     (n represents 0, 1 or 2, R 3  to R 13 , R 15  and R 16  each represents hydrogen or lower alkyl, and R 14  represents hydrogen, lower alkyl or lowver acyl.)!}

FIELD OF INDUSTRIAL APPLITCATION

This invention relates to a novel sulfonamide or sulfonic esterderivative, a process for producing the same and a medicinal compositioncomprising this compound as an active ingredient.

PRIOR ART

There have been a number of chemotherapeutic agents used for cancer, forexample, alkylating agents such as cyclophosphamide, antimetabolitessuch as methotrexate and fluorouracil, antibiotics such as adriamycin,mitomycin and bleomycin, vincristine and etoposide originating in plantsand metal complexes such as cisplatin. However each of these agentsexerts an insufficient antitumor effect. Thus there has been an urgentneed to develop a novel antitumor agent.

Further, there have been reported antitumor compounds of aromaticsulfonamide type such as 4-aminobenzenesulfonamide derivatives (JapanesePatent Publication No. 3093/1968), 2-sulfanilamide-quinoxalinederivatives (Japanese Patent Laid-Open No. 429/1987) andN-(2-anilino-3-pyridyl)benzenesulfonamide derivatives (Japanese PatentLaid-Open No. 39256/1993). No antitumor compound of aromatic sulfonicester type has been reported so far.

DISCLOSURE OF THE INVENTION

The present invention aims at providing novel sulfonamide derivativesand novel sulfonic ester derivatives each having excellent antitumoractivity and differing in the basic skeleton from the conventionalantitumor compounds. It further aims at providing processes forproducing these compounds and medicinal compositions comprising thesecompounds as an active ingredient.

In view of these aims, the present inventors have conducted extensivestudies to seek excellent antitumor compounds. As a result, they havefound that a novel sulfonamide derivative and a novel sulfonic esterderivative with a tricyclic structure have each excellent antitumoractivity and a low toxicity, thus completing the present invention.

Accordingly, the present invention relates to a sulfonamide derivativeor a sulfonic ester derivative represented by the following generalformula (I) or a pharmacologically acceptable salt thereof: ##STR3##wherein G represents an aromatic 5- or 6-membered ring having 1 or 2substituents;

L represents --N(R¹)--, wherein R¹ represents hydrogen or lower alkyl oroxygen; and

M represents a tricyclic structure selected from among those of thefollowing formulae (a), (b), (c), (d), (e) and (f); ##STR4## whereinrings A and B each represent each an optionally substituted unsaturated5- or 6-membered ring;

X represents --N(R²)--, wherein R² represents hydrogen or lower alkyl,or --NHCO--;

Y represents oxygen, --S(O)_(n) --, --C(R³)(R⁴)--, --C(O)--, --N(R⁵)--,--CH(R⁶)CH(R⁷)--, --C(R⁸)═C(R⁹)--, --N(R¹⁰)C(O)--, --C(O)N(R¹⁰)--,--N═C(R¹¹)--, --C(R¹¹)═N--, --OCH(R¹²)--, --CH(R¹²)O--, --S(O)_(n)CH(R¹³)--, --CH(R¹³)S(O)_(n) --, --N(R¹⁴)CH(R¹⁵)-- or --CH(R¹⁵)N(R¹⁴)--,wherein n represents 0, 1 or 2, R³, R⁴, R⁶, R⁷, R⁸ and R⁹ are the sameor different from one another and each represents hydrogen or loweralkyl, R⁵, R¹⁰, R¹¹, R¹², R¹³ and R¹⁵ each represents hydrogen or loweralkyl, and R¹⁴ represents hydrogen, lower alkyl or lower acyl; and

Z represents nitrogen or --C(R¹⁶)═, wherein R¹⁶ represents hydrogen orlower alkyl;

provided that a combination wherein G is 4-methylphenyl or4-methoxycarbonylaminophenyl, X in the tricyclic structure (a) of M is--N(R²)--and Y is oxygen or --S(O)_(n) --, wherein n is 0, is excludedtherefrom.

The present invention involves the following modes.

A sulfonamide derivative or a sulfonic ester derivative represented bythe following general formula (I-a) or a pharmacologically acceptablesalt thereof: ##STR5## wherein R³¹ represents hydrogen, halogen, loweralkyl, lower alkoxy, nitro, cyano or amino optionally substituted bylower alkyl;

R³² and R³³ are the same or different from each other and eachrepresents hydrogen, lower alkyl, lower alkoxy or halogen;

L represents --N(R³⁴)-- or oxygen, wherein R³⁴ represents hydrogen orlower alkyl; and

M represents a tricyclic structure selected from among those of thefollowing formulae (a), (b), (c), (d), (e) and (f): ##STR6## whereinrings A and B represent each an optionally substituted unsaturated 5- or6-membered ring;

X represents --N(R³⁵)-- or --NHCO--;

Y represents oxygen, sulfur, --S(O)--, --S(O₂)--, --C(R³⁶) (R³⁷)--,--C(O)--, --N(R³⁸)--, --CH₂ CH₂ --, --CH═CH--, --NHCO--, --CONH--,--CH═N--, --N═CH--, --CH₂ O--, --OCH₂ --, --CH₂ S--, --SCH₂ --, --CH₂N(R³⁹)--, --N(R⁴⁰)CH₂ --, --CH₂ S--(O)--, --S(O)CH₂ --, --CH₂ S(O₂)-- or--S(O₂)CH₂ --; and

Z represents nitrogen or C-R⁴¹ ;

wherein R³⁵, R³⁶, R³⁷, R³⁸, R³⁹ R⁴⁰ and R⁴¹ each represents hydrogen orlower alkyl;

provided that a combination wherein R³¹ is hydrogen or methyl, R³² andR³³ are each hydrogen, L is --N(R³⁴)--, X in the tricyclic structure (a)of M is --N(R³⁵)-- and Y is sulfur or oxygen is excluded therefrom.

The present invention further provides a medicinal compositioncomprising a pharmacologically efficacious dose of the above-mentionedsulfonamide derivative or sulfonic ester or a pharmacologicallyacceptable salt thereof and a pharmacologically acceptable filler, amethod of treating or preventing a tumor by administering theabove-mentioned sulfonamide derivative or sulfonic ester derivative orpharmacologically acceptable salt thereof in a pharmacologicallyefficacious dose to a patient actually or possibly having a tumor, theuse of the above-mentioned sulfonamide derivative or sulfonic ester or apharmacologically acceptable salt thereof as a medicine for treating orpreventing a tumor, and the application thereof to the production of theabove-mentioned medicine.

The present invention is efficacious in the treatment or prevention of,for example, nasopharyngeal cancer, pulmonary cancer, intestinal cancer,mammary cancer, uterus cancer, gastric cancer, ovarian cancer, livercancer and leukemia, and in the treatment or prevention of tumors ofthese cancers.

Now, the present invention will be described in greater detail.

The "aromatic 5- or 6-membered ring having 1 or 2 substituents"represented by G in the above general formula (I) means benzene,pyridine, thiophene or furan having 1 or 2 substituents. Examples of thesubstituent include halogen atoms, lower alkyl groups, lower alkoxygroups and amino groups optionally substituted by a lower alkyl group.

The rings A and B in the tricyclic structure represented by M in theabove general formula (I) may be either the same or different from eachother. The "optionally substituted unsaturated 5- or 6-membered ring"represented thereby means an optionally substituted unsaturated 5- or6-membered hydrocarbon or an unsaturated heterocycle having a nitrogen,oxygen or sulfur atom as a heteroatom. Major examples of the unsaturated5- or 6-membered ring include pyrrole, pyrazole, imidazole, thiophene,furan, benzene, pyridine, pyrimidine, pyrazine, and pyridazine.

The above-mentioned 5- or 6-membered ring may have 1 to 3 substituents.Examples of the substituent include halogen atoms, lower alkyl groupsoptionally substituted by a hydroxyl group, lower alkoxy groupsoptionally substituted by a hydroxyl group, a hydroxyl group, aminogroups optionally substituted by a lower alkyl group optionally having ahydroxyl group, lower acylamino groups, a cyano group, lower acyl groupsand an oxo group. When the substituent is a hydroxyl group or thesubstituent has a hydroxyl group therein, these hydroxyl groups may be aprotected one. Examples of the protected hydroxyl group include amethoxymethyloxy group, a tetrahydropyranyloxy group, a benzyloxy group,phosphoric esters, sulfuric esters, sulfonic esters (for example, estersof p-methoxy-benzenesulfonic acid or methanesulfonic acid), amino acidesters (for example, esters of glycine, alanine, leucine, tyrosine,aspartic acid, glutamic acid, lysine, arginine, proline, sarcosine,β-alanine and γ-aminobutyric acid), glycosides (for example, glucosideand glucuronide), carbamoyloxy groups optionally substituted by a loweralkyl group (for example, carbamoyloxy, methylcarbamoyloxy anddimethylcarbamoyloxy groups), lower acyloxy groups (for example, thosecarrying 1 to 5 carbon atoms such as formyloxy, acetoxy, propionyloxyand pivaloyloxy groups) and a benzoyloxy group.

In the definition of the substituents optionally carried by R¹ to R¹⁶, Gand the rings A and B in the above general formula (I), the term "loweralkyl" means linear or branched alkyl groups having from 1 to 6 carbonatoms such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl, tert-butyl, n-pentyl (amyl), isopentyl, neopentyl,tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, n-hexyl,isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl,1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl,1,3-dimethylbutyl, 2,3-dimethyl-butyl, 3,3-dimethylbutyl, 1-ethylbutyl,2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl,1-ethyl-l-methylpropyl and 1-ethyl-2-methylpropyl groups. Among thesegroups, methyl, ethyl, propyl and isopropyl groups may be cited aspreferable ones and, in particular, methyl and ethyl groups may be citedas the most desirable ones.

In the definition of the substituents optionally carried by G and therings A and B, the term "lower alkoxy" means those derived from theabove-mentioned lower alkyls, for example, methoxy, ethoxy, n-propoxy,isopropoxy, n-butoxy, isobutoxy and tert-butoxy groups. Among thesegroups, methoxy and ethoxy groups may be cited as preferable ones. Asthe halogen, fluorine, chlorine and bromine atoms may be cited.

In the definition of the substituents optionally carried by R¹⁴ and therings A and B, the term "lower acyl" means, for example, formyl, acetyl,propionyl, butyryl, isobutyryl and valeryl groups.

In some cases, the sulfonamide derivative or sulfonic ester derivativerepresented by the above general formula (I) forms a salt together withan acid or a base. These salts of the compound (I) also fall within thescope of the present invention. Examples of the salt with an acidinclude salts with inorganic acids such as hydrochloric, hydrobromic andsulfuric acids and those with organic acids such as acetic, lactic,succinic, fumaric, maleic, citric, benzoic, methanesulfonic andp-toluenesulfonic acids. Examples of the salt with a base includeinorganic salts such as sodium, potassium and calcium salts and saltswith organic bases such as triethylamine, arginine and lysine.

It is needless to say that all of the hydrates of these compounds andoptical isomers thereof, if any, also fall within the scope of thepresent invention. The compounds of the present invention exhibit apotent antitumor activity and those which exhibit an antitumor activityafter being metabolized (i.e., oxidized, reduced, hydrolyzed,conjugated, etc.) in vivo are also included in the scope of the presentinvention. Further, compounds which are metabolized in vivo and thusform the compounds of the present invention are included in the scope ofthe present invention.

The compounds (I) of the present invention can be produced by variousmethods. Typical examples of these methods are as follows.

(1) A sulfonic acid represented by the following general formula (II):

    Gb--SO.sub.3 H                                             (II)

wherein

Gb represents optionally protected G; or a reactive derivative thereofis reacted with a compound represented by the following general formula(III):

    H--L--Ma                                                   (III)

wherein

L has the same meaning as the one defined above; and

Ma represents optionally protected M. When the compound thus obtainedhas a protecting group, it may be removed, if desired. Thus the targetcompound can be obtained.

Examples of the reactive derivative of the sulfonic acid (II) includethose commonly employed in the art, for example, sulfonyl halides,sulfonic anhydride and N-sulfonylimidazolides may be cited. Asparticularly preferable examples thereof, sulfonyl halides may be cited.This reaction proceeds at the stoichiometrically equimolar ratio.Although the solvent to be used in the reaction is not particularlyrestricted, it is desirable to use a solvent in which the startingcompounds are soluble and which would not easily react with them. Forexample, pyridine, tetrahydrofuran, dioxane, benzene, ether,dichloromethane, dimethylformamide, or a mixture of two or more solventsselected therefrom may be employed as the solvent. In such a case as theone with the use of a sulfonyl halide where an acid is liberated withthe progress of the reaction, it is preferable to effect the reaction inthe presence of an appropriate deacidifying agent. In such a case, it isparticularly suitable to use a basic solvent such as pyridine. When aneutral solvent is employed, a basic substance (for example, an alkalicarbonate or an organic tertiary amine) may be added. As a matter ofcourse, the solvents usable in this reaction are not restricted to thosecited above. Although this reaction generally proceeds at roomtemperature, the reaction system may be cooled or heated, if necessary.The reaction time usually ranges from 10 minutes to 20 hours, though itcan be arbitrarily selected depending on the employed starting compoundsand the reaction temperature.

When the product thus obtained has a protected amino or hydroxyl group,the protecting group may be removed by a conventional method such as atreatment with an acid or a base or catalytic reduction, if desired.Thus a sulfonamide derivative or a sulfonic ester derivative (I) havinga free hydroxyl or amino group can be obtained.

(2) A compound represented by the following general formula (VII):##STR7## wherein Gb and Ma have each the same meaning as the one definedabove; is reacted with a lower alkyl halide in the presence of a basesuch as sodium hydride to thereby give the target compound. When theproduct thus obtained has a protected amino or hydroxyl group, theprotecting group may be removed by a conventional method such as atreatment with an acid or a base or catalytic reduction, if desired.Thus a sulfonamide derivative (I) having a free hydroxyl or amino groupcan be obtained.

(3) A compound represented by the following general formula (VIII):##STR8## wherein Gb and L have each the same meaning as the one definedabove; and

Mb represents Ma as defined above wherein Y contains a sulfur atom; isreacted with an oxidizing agent such as hydrogen peroxide orm-chloroperbenzoic acid to thereby give the target compound. When theproduct thus obtained has a protected amino or hydroxyl group, theprotecting group may be removed by a conventional method such as atreatment with an acid or a base or catalytic reduction, if desired.Thus a sulfonamide derivative or a sulfonic ester derivative (I) havinga free hydroxyl or amino group can be obtained.

(4) A compound represented by the following general formula (IV):##STR9## wherein Gb, R¹ and R² have each the same meaning as the onedefined above;

R^(14a) represents hydrogen or lower alkyl; and

rings Aa and Ba represent respectively the rings A and B which areoptionally protected; is reacted with an aldehyde such asparaformaldehyde or acetaldehyde in the presence of an acid such ashydrochloric acid or hydrobromic acid to thereby give the targetcompound. Although the solvent to be used in this reaction is notparticularly restricted, tetrahydrofuran, methanol, water or a mixturethereof may be used therefor. The reaction temperature can bearbitrarily selected depending on the starting compounds and thereaction system may be heated, if necessary. When the product thusobtained has a protected amino or hydroxyl group, the protecting groupmay be removed by a conventional method such as a treatment with an acidor a base or catalytic reduction, if desired. Thus a sulfonamidederivative (I) having a free hydroxyl or amino group can be obtained.

(5) A compound represented by the following general formula (IVa):##STR10## wherein Gb, R¹ and rings Aa and Ba have each the same meaningas the one defined above;

R^(2a) represents lower alkyl or a protecting group; and

R^(14b) represents lower acyl; is reacted in the presence of, forexample, polyphosphoric acid or phosphorus oxychloride to thereby givethe target compound. The reaction temperature can be arbitrarilyselected depending on the starting compounds and the reaction system maybe heated, if necessary. When the product thus obtained has a protectedamino or hydroxyl group, the protecting group may be removed by aconventional method such as a treatment with an acid or a base orcatalytic reduction, if desired. Thus a sulfonamide derivative (I)having a free hydroxyl or amino group can be obtained.

(6) A compound represented by the following general formula (IX):##STR11## wherein Gb, R¹, R², R¹⁰ and rings Aa and Ba have each the samemeaning as the one defined above; and

J represents carboxyl or a reactive derivative thereof; is subjected tointramolecular ring closure to thereby give the target compound. Thereaction temperature can be arbitrarily selected depending on thestarting compounds and the reaction system may be cooled or heated, ifnecessary. Examples of the reactive derivative of carboxyl includeesters, active esters, acid halides, acid anhydrides and active amidecompounds. When the carboxyl group is to be used as such, the reactioncan be effected in the presence of a condensing agent such as1,3-dicyclohexylcarbodiimide (DCC) or diphenylphosphoryl azide (DPPA).When the product thus obtained has a protected amino or hydroxyl group,the protecting group may be removed by a conventional method such as atreatment with an acid or a base or catalytic reduction, if desired.Thus a sulfonamide derivative (I) having a free hydroxyl or amino groupcan be obtained.

(7) A compound represented by the following general formula (V):##STR12## wherein Gb, R¹, R², R¹⁴, R¹⁵ and rings Aa and Ba have each thesame meaning as the one defined above; and

V represents a leaving group; is subjected to intramolecular ringclosure to thereby give the target compound. Examples of the leavinggroup V include halogen atoms and methanesulfonylxoy andp-toluenesulfonyloxy groups. It is not always necessary that thestarting compound (V) be one which can be isolated. Namely, it may betemporarily formed as, for example, a reaction intermediate. When theproduct thus obtained has a protected amino or hydroxyl group, theprotecting group may be removed by a conventional method, if desired.Thus a sulfonamide derivative (I) having a free hydroxyl or amino groupcan be obtained.

(7) A compound represented by the following general formula (VI):##STR13## wherein Gb, R¹, R² and rings Aa and Ba have each the samemeaning as the one defined above; and

Ya represents NHCO-- or --N═C(R¹¹, (wherein R¹¹ has the same meaning asthe one defined above; is reduced to thereby give the target compound.The reduction may be performed by a method arbitrarily selecteddepending on the starting compound. For example, catalytic reduction orreduction with the use of a metal hydride such as lithium aluminumhydride may be cited therefor. When the product thus obtained has aprotecte d amino or hydroxyl group, the protecting group may be removedby a conventional method, if desired. Thus a sulfonamide derivative (I)having a free hydroxyl or amino group can be obtained.

Now, processes for producing the starting compounds to be used in thepresent invention will be illustrated.

The starting compound H-L-Ma (III) includes known compounds and novelones. When H-L- in the starting compound (III) represents an amino group(H₂ N--), H₂ N-Ma (III) can be obtained by reducing the nitro compoundO₂ N-Ma by a method commonly employed for reducing a nitro group.Preferable examples of the reduction method include catalytic reductionwith the use of palladium-carbon as the catalyst and reduction with zincdust-acetic acid. The catalytic reduction can usually be effected in anorganic solvent such as methanol, tetrahydrofuran or dimethylformamideunder atmospheric or elevated pressure.

When H-L in the starting compound (III) represents a hydroxyl group,HO-Ma (III) can be obtained through the diazotization of theabove-mentioned H₂ N-Ma followed by hydrolysis.

Alternatively, the starting compound (III) can be obtained by removingthe protecting group Q in a compound represented by the followinggeneral formula (X): ##STR14## wherein R¹ and Ma have each the samemeaning as the one defined above; and

Q represents a protecting group for the amino group by an appropriatemethod. Examples of the protecting group for the amino group incl udebeIzyloxycarhonyl, method for removing the protecting group variesdepending on the type of this group. For example, catalytic reduction, atreatment with an acid or a treatment with an alkali may be employedtherefor.

Next, methods for producing the nitro compound O₂ N-Ma and Q-N(R¹)-Ma(X), from which the starting compound (III) is produced, will beillustrated. Also, these compounds can be produced by referring to, forexample, synthesis examples of various tricyclic compounds described inThe Chemistry of Heterocyclic Compounds, Vol. 9, Vol. 47 and Vol. 47,Part 2. Production process 1: ##STR15## wherein rings Aa and Ba and R²have each the same meaning as the one defined above;

E represents nitro or protected amino; and

D represents a leaving group such as halogen or nitro.

The compound represented by the general formula (XIV) can be produced bymethods described in various publications, for example, the methoddescribed in J. Med. Chem., 35, 4770 or a method similar thereto.Specifically, the compound represented by the general formula (XI) isheated together with the amine (XII) in N,N-dimethylaniline employed asa solvent in the presence or absence of N,N-diisopropylethylamine. Thethus obtained compound (XIII) is then subjected to ring closure byreacting with phosphorus oxychloride in a solvent such as1,2-dichloroethane in the presence of N,N-dimethylaniline under heatingor by heating in conc. sulfuric acid. Thus the target compound can besynthesized.

Similarly, the compound represented by the general formula (XIV) can besynthesized via the following route too. ##STR16## wherein rings Aa andBa, R², E and D have each the same meaning as the one defined above.

The compound (XV) can be produced by reacting the compound (XIV) with areducing agent such as lithium aluminum hydride-aluminum chloride.Production process 2: ##STR17## wherein rings Aa and Ba, R², D and Ehave each the same meaning as the one defined above;

W represents a leaving group such as halogen or nitro; and

Yb represents oxygen, sulfur, --N(R⁵)--, --OCH(R¹²)--, --SCH(R¹³)-- or--N(R¹⁴)CH(R¹⁵)--, wherein R⁵, R¹², R¹³, R¹⁴ and R¹⁵ have each the samemeaning as the one defined above.

The compound represented by the general formula (XXI) can be produced bymethods described in various publication, for example, those describedin J. Chem. Soc., (1953) 1504; J. Org. Chem., 25, 60; and J. Chem. Soc.(C), (1969), 2148 or a method similar thereto. Specifically, it can besynthesized by heating the compound represented by the general formula(XIX) and the compound represented by the general formula (XX) or itsN-formyl derivative in dimethylformamide in the presence of potassiumcarbonate and a catalytic amount of a copper powder. Alternatively, itcan be synthesized by first reacting the compound represented by thegeneral formula (XIX) with the compound represented by the generalformula (XX) in the presence or absence of sodium acetate ortriethylamine at room temperature or under heating, then adding, forexample, potassium carbonate or caustic soda thereto and reacting themixture in the presence or absence of a copper powder at roomtemperature or under heating. Production process 3: ##STR18## whereinrings Aa and Ba and Y have each the same meaning as the one definedabove.

The compound represented by the general formula (XXIII) can besynthesized by, for example, the method described in Synthesis,215(1988) or a method similar thereto. Namely, the compound representedby the general formula (XXII) is reacted with n-butyllithium in asolvent such as tetrahydrofuran. After blowing carbon dioxide thereinto,the reaction product is reacted successively with n-butyllithium andisobutyl nitrate. Thus the compound represented by the general formula(XXIII) can be synthesized. Production process 4: ##STR19## whereinrings Aa and Ba, X, Y and Z have each the same meaning as the onedefined above.

The compounds represented by the general formulae (XXV), (XXVII), (XXIX)and (XXXI) can be synthesized respectively through the nitration of thecompounds (XXIV), (XXVI), (XXVIII) and (XXX) each by a conventionalmethod with the use of a nitrating agent commonly employed in the art,for example, conc. nitric acid, fuming nitric acid, mixed acid or acetylnitrate. In the case of the compound (XXIVa), i.e., the one of thegeneral formula (XXIV) wherein X represents NH, the corresponding nitrocompound can be synthesized by the method described in Aust. J. Chem.,25, 2451 or a method similar thereto, i.e., through the N-nitrosation ofthe compound (XXIVa) with nitrous acid followed by light irradiation inthe presence of oxygen. Production process 5: ##STR20## wherein rings Aaand Ba, E, D and Yb have each the same meaning as the one defined above.

The compound represented by the general formula (XXXVI) can be producedby the method described in Chem. Ind., 825(1985) or a method similarthereto. Specifically, the compound represented by the general formula(XXXII) and the compound (XXXIII) are heated in a solvent such asdimethylformamide or ethanol in the presence of, for example, potassiumcarbonate and a copper powder or potassium iodide. Then the compound(XXXIV) thus obtained is reduced by a method commonly employed forreducing a nitro group. The obtained amine (XXXV) is then heated ortreated with a condensing agent such as 1,3-dicyclohexylcarbodiimide.Thus the compound (XXXVI) can be synthesized.

Also, the compound represented by the general formula (XXXVI) can beproduced via the following route, wherein an amide bond is first formedfollowed by ring closure, as described in, for example, J. LabelledCompd. Radiopharm., 20, 1399. ##STR21## wherein rings Aa and Ba, E, Dand Yb have each the same meaning as the one defined above. Productionprocess 6: ##STR22## wherein rings Aa and Ba, R² and Gb have each thesame meaning as the one defined above; and

U represents a leaving group.

The compound represented by the general formula (XLV) can be synthesizedfrom the dinitrohalide (XI) through a reaction with the amine (XLI),reduction and another reaction with the sulfonyl chloride (XLIV).

When the compound of the present invention is to be used as a medicine,it can be orally or parenterally administered. Although the dose of thecompound is not particularly restricted, but varies depending on theseverity of the conditions, the age, sex, body weight and sensitivity ofthe patient, the route, period and interval of the administration, andthe properties, compounding, type and active ingredients of themedicinal preparation, it may be administered to an adult in a dailydose of from 10 to 6,000 mg, preferably from about 50 to 4,000 mg andstill preferably from 100 to 3,000 mg, usually once to thrice a day.

To prepare a solid preparation for oral administration, the principalagent is blended with fillers optionally together with binders,disintegrators, lubricants, coloring agents, corrigents, etc. Then theobtained blend is formed into, for example, tablets, coated tablets,granules, fine subtilaes, dusts or capsules by a conventional method.

Usable fillers are, for example, lactose, corn starch, sucrose, glucose,sorbitol, crystalline cellulose and silicon dioxide. Usable binders are,for example, polyvinyl alcohol, ethylcellulose, methylcellulose, acacia,hydroxypropylcellulose and hydroxypropylmethylccllulose. Usablelubricants are, for example, magnesium stearate, talc and silica. Usablecoloring agents are those authorized as medicinal additives. Usablecorrigents are, for example, cocoa powder, menthol, aromatic powder,mentha oil, borneol and powdered cinnamon bark. As a matter of course,these tablets and granules may be coated with sugar, gelatin, etc., ifdesired.

To prepare an injection, the principal agent is blended optionally withpH regulators, buffer agents, suspending agents, solubilizing agents,stabilizers, tonicity agents, preservatives, etc. Then the obtainedblend is formed into intravenous, subcutaneous or intramuscularinjections by a conventional method. If necessary, it may be formed intoa freeze-dried preparation in a conventional manner.

Examples of the suspending agents include methylcellulose, polysorbate80, hydroxyethyl-cellulose, acacia, powdered tragacanth,carboxy-methylcellulose sodium and polyoxyethylenesorbitan monolaurate.

Examples of the solubilizing agents include polyoxyethylene hardenedcastor oil, polysorbate 80, nicotinamide, polyoxyethylenesorbitanmonolaurate, Macrogol and castor oil fatty acid ethyl ester.

As the stabilizers, for example, sodium sulfite and sodium metasulfiteare usable. Examples of the preservatives include methylparahydroxybenzoate, ethyl parahydroxybenzoate, sorbic acid, phenol,cresol and chlorocresol.

To illustrate the effects of the compounds of the present invention, thefollowing pharmacological experiment examples will be given.

Experimental Example 1

in vitro Antitumor test on KB cells (human nasopharyngeal cancer cells)

KB cells suspended in an RPMI1640 medium (mfd. by Nissui Seiyaku K. K.),which contained 10% of fetal calf serum, 100 U/mi of penicillin, 100μg/ml of streptomycin, 5×10⁻⁵ M of mercaptoethanol and 1 mM of sodiumpyruvate, were inoculated in 1.25×10³ portions (0.1 ml) into wells of a96-well flat-bottomed microplate and then incubated in an incubatorcontaining 5% of carbon dioxide at 37° C. for a day.

A compound of the present invention was dissolved in dimethyl sulfoxidein a concentration of 20 mg/ml and diluted with a 10% fetal calfserum-RPMI1640 culture medium to a concentration of 100 μg/ml. By usingthis concentration as the highest level, threefold serial dilution wasperformed with a 10% fetal calf serum-RPMI1640 culture medium. Then itwas added in 0.1 ml portions into the wells of the above-mentioned platewherein the KB cells had been incubated followed by incubation in theincubator containing 5% of carbon dioxide at 37° C. for 3 days.

After incubating, an MTT(3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) solution(3.3 mg/ml) was added in 0.05 ml portions into the wells and theincubation was effected for additional 1 hour. After sucking off thesupernatant from each well, the formazane thus formed was dissolved in0.1 ml of dimethyl sulfoxide. Then the absorbance at 540 nm was measuredwith a microplate reader and employed as an indication of the vital cellcount. In accordance with the following equation, the inhibitory ratiowas calculated and the 50% inhibitory concentration (IC₅₀) of the testcompound was determined. ##EQU1## T: absorbance of a well containing thetest commpound. C: absorbance of a well containing no test compound.

Table 1 shows the IC₅₀ data thus obtained.

                  TABLE 1                                                         ______________________________________                                        in vitro Antitumor test on KB cells                                           Compd. (Exp. Ex. no.)                                                                          IC.sub.50 (μg/ml)                                         ______________________________________                                         1               0.11                                                          2               0.10                                                          4               0.17                                                          5               0.08                                                          6               0.09                                                          9               0.23                                                         12               0.25                                                         14               0.026                                                        15               0.15                                                         16               0.022                                                        17               0.03                                                         20               0.11                                                         22               0.17                                                         24               0.0061                                                       25               0.016                                                        26               0.15                                                         28               0.069                                                        29               0.11                                                         30               0.028                                                        31               0.27                                                         32               0.082                                                        33               0.043                                                        34               0.25                                                         35               0.25                                                         38               0.047                                                        39               0.26                                                         40               0.032                                                        41               0.28                                                         42               0.13                                                         43               0.22                                                         44               0.077                                                        45               0.016                                                        46               0.25                                                         47               0.078                                                        48               0.028                                                        49               0.08                                                         ______________________________________                                    

Experimental Example 2

in vivo antitumor test on M5076 (mouse reticulum cell sarcoma)

1×10⁶ M5076 cells were subcutaneously transplanted into the lateralparts of BDF₁ mice (aged 6 to 9 weeks, female). A compound of thepresent invention was suspended in physiological saline containing 3.5%of dimethyl sulfoxide and 6.5% of Tween 80 and a given amount of theobtained suspension was intraperitoneally administered to the animals 4times from the 10th day after the transplantation once a day every otherday. The control group comprised 10 to 12 animals, while the test groupcomprised 5 or 6 animals.

On the 21st day after the transplantation, tumors were taken out andweighed. Then the tumor multiplication inhibitory ratio of each testgroup based on the control group was determined in accordance with thefollowing equation. ##EQU2## T: average tumor weight of the test group.C: average tumor weight of the control group.

Table 2 shows the results thus obtained.

                  TABLE 2                                                         ______________________________________                                        in vivo Antitumor test on M5076                                               Compd.   Dose         Inhibitory                                                                             Survival ratio                                 (Exp. Ex. no.)                                                                         (mg/kg/day)  ratio (%)                                                                              on 21st day (%)                                ______________________________________                                         1       50           73       100                                            17       100          81       100                                            28        50          82       100                                            30       100          82       100                                            32        25          84       100                                            ______________________________________                                    

As the above experimental examples show, the compounds of the presentinvention have each an excellent antitumor effect and is highly usefulas an antitumor agent.

EXAMPLES

Next, Production Examples for showing processes for the production ofthe starting compounds for the compounds of the present invention andExamples for showing representative examples of the compounds of thepresent invention will be given. However it is to be understood that thepresent invention is not restricted thereto. When the compound describedin the production example was a tricyclic compound having a nitro group,the nitro group was reduced into an amino group via catalytic reductionwith the use of a catalyst such as palladium-carbon or platinum oxide orreduction effected by adding hydrochloric acid or acetic acid to zinc,iron, etc., and then the resulting compound was reacted with an aromaticsulfonyl chloride to thereby give the compound described in thecorresponding example.

Production Example 1

2-Benzyloxy-5-nitro-9 (10H)-acrdinone ##STR23##

A mixture comprising 2.2 g (11 mmol) of 4-benzyl-oxyaniline, 2.0 g (10minol) of 2-chloro-3-nitrobenzoic acid, 6 ml of N,N-dimethylaniline and1.6 ml of N,N-diisopropylethylamine was heated at 100° C. for 12 hoursunder stirring. After cooling, 30 ml of chloroform and 30 ml of 1Nsodium hydroxide were added thereto. The precipitate thus formed wasseparated by filtration, stirred together with 5% hydrochloric acid andwashed with water to thereby give 3.3 g of2-((4-benzyloxyphenyl)amino)-3-nitrobenzoic acid. This product was addedto 40 ml of chloroform and 0.3 ml of N,N-dimethylaniline and 6 ml ofphosphorus oxychloride were further added thereto. After heating underreflux for 30 minutes and then cooling, the crystals thus precipitatedwere separated by filtration. Thus 2.1 g of the title compound wasobtained.

¹ H-NMR(DMSO-d₆) δ (ppm): 5.22(2H, s), 7.33(1H, t, J=8.0 Hz),7.36-7.42(3H, m), 7.49(2H, d, J=8.0 Hz), 7.54(1H, dd, J=9.2, 2.8 Hz),7.69(1H, d, J=2.8 Hz), 8.08(1H, d, J=9.2 Hz), 8.65-8.69(2H, m), 11.5(1H,br s)

Production Example 2

7-Fluoro-1-nitro-10H-phenothiazine ##STR24##

2.2 g (15 mmol) of 2-amino-5-fluorobenzenethiol was dissolved in 30 mlof dimethylformamide and 2.5 g (12 mmol) of 1-chloro-2,6-dinitrobenzenewas added thereto. The resulting mixture was stirred at roomtemperature. After 12 hours, 2.6 ml of N,N-diiso-propylethylamine wasadded thereto and the mixture was heated at 80° C. for 2 hours. Aftercooling, the reaction mixture was poured into a saturated aqueoussolution of ammonium chloride and extracted with ethyl acetate. Afterconcentrating, the residue was purified by silica gel columnchromatography. Thus 1.2 g of the title compound was obtained.

¹ H-NMR(CDCl₃) δ (ppm): 6.64(1H, dd, J=8.8, 4.8 Hz), 6.70(1H, dd, J=8.0,2.8 Hz), 6.73-6.80(2H, m), 7.12-7.15(1H, m), 7.90(1H, dd, J=9.2, 1.4Hz), 9.66(1H, br s)

Production Example 3

4-Amino-5H-dibenz b,f!azepine ##STR25##

1 g (5.2 mmol) of 5H-dibenz(b,f)azepine was suspended in 40 ml of dryether and 9.7 ml (15.5 mmol) of a 1.6M solution of n-butyllithium inhexane was dropped thereinto under stirring at room temperature. After24 hours, the reaction mixture was cooled in a dry ice-acetone bath and2 ml of a solution of 0.93 g (7.8 mmol) of isobutyl nitrate in dry etherwas dropped thereinto. After stirring at room temperature for 30minutes, 2 ml of acetic acid was added thereto. Then the reactionmixture was poured into 50 ml of water and extracted with ethyl acetate.The organic layer was washed with water, dried over magnesium sulfateand concentrated. Then the residue was purified by silica gel columnchromatography to thereby give 4-nitro-5H-dibenzt(b,f)azepine. Thisproduct was dissolved in 50 ml of tetrahydrofuran and 1 g of zinc dustwas added. Under stirring, conc. hydrochloric acid was droppedthereinto. When the reaction mixture turned from reddish brown into paleyellow, the addition was ceased and the formed insoluble matters werefiltered off. The filtrate was made basic by adding diluted aqueousammonia and then extracted with ethyl acetate. The organic layer waswashed with water, dried over magnesium sulfate and concentrated and theresidue was purified by silica gel column chromatography. Thus 45 mg ofthe title compound was obtained.

Production Example 4

7-Hydroxy-1-nitro-10H-phenoxazine ##STR26##

6 g (30 mmol) of 1-chloro-2,6-dinitrobenzene and 4.8 g (30 mmol) of4-aminoresorcinol hydrochloride were added to 300 ml of a mixture oftetrahydrofuran with dimethylformamide (1:1). After adding 7.8 g (60mmol) of N,N-diisopropylethylamine thereto, the obtained mixture wasstirred at room temperature for 24 hours. Then the solvent was distilledoff under reduced pressure and the residue was dissolved in ethylacetate and washed with a saturated aqueous solution of sodium chloride.Then it was dried over magnesium sulfate and concentrated and theresidue was purified by silica gel column chromatography. Thus 6.95 g of4-((2,6-dinitrophenyl)amino) resorcinol was obtained. This product wasdissolved in 125 ml of dimethylformamide and 25 ml ofN,N-diisopropylethyl-amine was added thereto. After heating at 100° C.for 2 hours, the reaction mixture was concentrated and the residue wasdissolved in ethyl acetate, washed with water, dried over magnesiumsulfate and concentrated to dryness. Thus 5.4 g of the title compoundwas obtained.

Production Example 5

7-(tert-Butyldimethysilyloxy)-1-nitro-10H-phenoxazine ##STR27##

1.2 g (4.9 mmol) of the compound of Production Example 4, 1.1 g (7.4mmol) of tert-butyldimethylsilyl chloride and 0.5 g (7.4 mmol) ofimidazole were dissolved in 50 ml of dimethylformamide and stirred in anitrogen atmosphere at room temperature for 8 hours. Afterconcentrating, the residue was dissolved in 500 ml of diethyl ether,washed with water, dried over magnesium sulfate and concentrated. Theresidue was purified by silica gel column chromatography. Thus 1.15 g ofthe title compound was obtained.

Production Example 6

5,11-Dihydro-6-nitrodibenz(b,e)(1,4)oxazepine ##STR28##

2.85 g (14 mmol) of 1-chloro-2,6-dinitrobenzene and 1.73 g (14 mmol) of2-aminobenzyl alcohol were dissolved in 30 ml of triethylamine andheated under reflux for 24 hours. After concentrating, the residue waspurified by silica gel column chromatography. Thus 2.2 g of2-((2,6-dinitrophenyl)amino) benzyl alcohol was obtained. 0.29 g (1mmol) of this powder was dissolved in 20 ml of dry dimethylformamide.After adding 40 mg (1 mmol) of sodium hydride (in oil, content: 60%),the reaction mixture was stirred at room temperature for 15 minutes andthen at 150° C. for 2 hours. After cooling, 200 ml of ethyl acetate wasadded thereto and the mixture was washed with water, dried overmagnesium sulfate and concentrated. The residue was purified by silicagel column chromatography. Thus 0.14 g of the title compound wasobtained.

Production Example 7

9-Nitrodihenz b f! 1,4!oxazepin-11(10H)-one ##STR29##

1.57 g (10 mmol) of 2-amino-3-nitrophenol was dissolved in 20 ml ofpyridine and 3.36 g (21 mmol) of 2-fluorobenzoyl chloride was addedthereto under stirring. After heating under reflux for 4 hours, themixture was concentrated. Then dilute hydrochloric acid and ethylacetate were added thereto. The organic layer was separated and washedwith water. After concentrating, 20 ml of tetrahydrofuran and 20 ml of1N sodium hydroxide were added and the mixture was heated under refluxfor 4 hours. After cooling, it was neutralized with hydrochloric acidand concentrated. After adding ethyl acetate and water, the organiclayer was separated, washed with water and dried over magnesium sulfate.After concentrating, the residue was purified by silica gel columnchromatography. Thus 2.35 g of2-fluoro-N-(2-hydroxy-6-nitrophenyl)benzamide was obtained. 553 mg (2mmol) of this powder was dissolved in 20 ml of dimethylformamide and 332mg (2.4 mmol) of potassium carbonate and 20 mg of a copper powder wereadded thereto. After heating under reflux for 3 hours and concentrating,ethyl acetate and dilute hydrochloric acid were added to the residue.The formed insoluble matters were filtered off and the organic layer wasseparated, washed with water, dried over magnesium sulfate andconcentrated. Then the residue was purified by silica gel columnchromatography. Thus 400 mg of the title compound was obtained.

M.p.: 162°-163° C.

Production Example 8

9,10-Dihydro-4-nitroaceidine ##STR30##

1.361 g (10 mmol) of aluminum chloride was dissolved in 10 ml of drytetrahydrofuran. To the solution thus obtained was slowly added 75 ml ofa solution of 1.201 g (5 mmol) of 4-nitro-9(10H)-acridinone in drytetrahydrofuran. After stirring at room temperature for 30 minutes, 759mg (20 mmol) of lithium aluminum hydride was added thereto in portions.After stirring at room temperature for 30 minutes and then at 55° C. foradditional 30 minutes, the reaction mixture was cooled to roomtemperature and 5 ml of 1N hydrochloric acid was added thereto. Afterconcentrating, ethyl acetate and water were added to the residue and theformed insoluble matters were filtered off. The organic layer wasseparated from the filtrate and dried over magnesium sulfate. Afterconcentrating, the residue was purified by silica gel columnchromatography. Thus 148 mg of the title compound was obtained.

¹ H-NMR(CDCl₃) δ (ppm): 5.23(2H, br), 6.94(1H, dd, J=5.6, 2.8 Hz),7.32-7.38(2H, m), 7.48-7.55(1H, m), 7.69-7.75(1H, m), 7.94-8.00(1H, m)8.18-8.24(1H, m), 8.67(1H, s)

Production Example 9

5,11-Dihydro-6-nitrodibenzo (b,e)(1,4) thiazepine ##STR31##

1.8 g (6.2 mmol) of 2- (2,6-dinitrophenyl)amino!-benzyl alcohol wasdissolved in a mixture of 50 ml of dictloromethane with 50 ml of ethylether. Under ice-cooling and stirring, 2.2 ml (15.5 mmol) oftriethylamine and 0.58 ml (7.4 mmol) of methane-sulfonuyl chloride weresuccessively added thereto. After stirring for 30 minutes, the reactionmixture was poured into a saturated aqueous solution of ammoniumchloride and extracted with ethyl acetate. After concentrating, theresidue was dissolved in 150 ml of acetone. Then 2.7 g (31 mmol) oflithium bromide was added and the resulting mixture was heated underreflux for 1 hour. After distilling off the solvent under reducedpressure, the residue was purified by silica gel column chromatographyto thereby give 0.5 g of 2((2,6-dinitrophenyl)amino)-benzyl bromide.This product was dissolved in 10 ml of dimethylformamide. After adding216 mg (2.8 mmol) of thiourea, the mixture was stirred at roomtemperature for 5 hours. Then 10 ml of dimethylformamide, 157 mg (2.8mmol) of potassium hydroxide and 2 ml of water were successively addedthereto and the reaction mixture was heated at 100° C. for 3 hours.After cooling, the reaction mixture was poured into a saturated aqueoussolution of sodium chloride and extracted with ethyl acetate. Afterconcentrating, the residue was purified by silica gel columnchromatography. Thus 0.22 g of the title compound was obtained.

¹ H-NMR(CDCl₃) δ (ppm): 4.02(2H, s), 6.73(1H, dd, J=8.8, 7.6 Hz),6.94(1H, dt, J=7.6, 1.2 Hz), 7.06(1H, dd, J=7.6, 1.6 Hz), 7.09(1H, dd,J=7.6, 1.2 Hz), 7.22(1H, dt, J=7.6, 1.6 Hz), 7.55(1H, dd, J=7.6, 1.6Hz), 8.17(1H, dd, J=8.8, 1.6 Hz), 11.13(1H, br s)

Production Example 10

N² -(4-Methylphenyl)-1,2,3-triaminobenzene ##STR32##

0.8 g (7.4 mmol) of p-toluidine and 1.5 g of 1-chloro-2,6-dinitrobenzenewere dissolved in 15 ml of dimethyl sulfoxide and 1.5 g (14.8 mmol) oftriethylamine was added thereto. After stirring at 80° to 90° C. for 12hours, ethyl acetate was added and the reaction mixture was washed withwater and dried over magnesium sulfate. After concentrating, the residuewas purified by silica gel column chromatography. Thus 2.0 g ofN-(4-methylphenyl)-2,6-dinitroaniline was obtained. This product wasdissolved in a mixture of 20 ml of methanol with 40 ml oftetrahydrofuran and hydrogenated in the presence of palladium-carbon atroom temperature under atmospheric pressure. After filtering off thecatalyst, the solvent was distilled off under reduced pressure. Thus 1.6g of the title compound was obtained.

¹ H-NMR(CDCl₃) δ (ppm): 2.25(3H, s), 3.75(4H, br), 4.68(1H, br s),6.23(2H, d, J=8.0 Hz), 6.56(2H, dd, J=8.0, 2.0 Hz), 6.92(1H, t, J=8.0Hz), 6.99(2H, d, J=8.0 Hz)

Production Example 11

N-(3-Amino-2-((4-methylphenyl)amino)phenyl)-4-methoxybenzenestllfonami(ie##STR33##

1.6 g (7.4 mmol) of the compound of Production Example 10 was dissolvedin 40 ml of tetrahydrofuran. Then 5.6 ml of pyridine and 1.7 g (8.1mmol) of 4-methoxybenzenesulfonyl chloride were successively addedthereto. After stirring at room temperature for 12 hours, ethyl acetatewas added. The reaction mixture was washed with water, dried overmagnesium sulfate and concentrated. Then the residue was purified bysilica gel column chromatography. Thus 1.8 g of the title compound wasobtained.

¹ H-NMR(CDCl₃) δ (ppm): 2.24(3H, s), 3.65(2H, br), 3.85(3H, s), 4.62(1H,br s), 6.28(2H, d, J=8.4 Hz), 6.49(1H, dd, J=8.0, 1.6 Hz), 6.86(2H, d,J=8.8 Hz), 6.90(2H, d, J=8.4 Hz), 6.96(2H, dd, J=8.0, 1.6 Hz), 7.02(1H,t, J=8.0 Hz), 7.22(1H, br s), 7.67(2H, d, J=8.8 Hz)

Production Example 12

2-((2,6-Dinitrophenyl)amino)-5-fluorobenzoic acid ##STR34##

3.0 g (19.3 mmol) of 2-amino-5-fluorobenzoic acid and 5.88 g (29.0 mmol)of 1-chloro-2,6-dinitrobenzene were dissolved in a mixture of 30 ml ofdimethyl-formamide with 30 ml of dimethyl sulfoxide. After adding 6.74ml of triethylamine, the reaction mixture was stirred in a nitrogenatmosphere at room temperature for 14 days and concentrated followed bythe addition of 1N hydrochloric acid thereto. Then it was extracted withethyl acetate, washed with 1N hydrochloric acid and dried over magnesiumsulfate. After concentrating, chloroform was added thereto. The crystalsthus precipitated were collected. Thus 2.65 g of the title compound wasobtained.

¹ H-NMR(DMSO-d₆) δ (ppm): 6.88(1H, dd, J=9.2, 4.4 Hz), 7.29-7.4(1H, m) ,7.37(1H, t, J=8.0 Hz), 7.64(1H, dd, J=9.2, 3.2 Hz), 8.35(2H, d, J=8.0Hz), 10.70(1H, s), 13.87(1H, br s)

Production Example 13

6-Amino-5,10-dlihydro-2-fliloro-11H-dibenzo(b,e)(1,4)-diazepin-11-one##STR35##

2.5 g (7.8 mmol) of the compound of Production Example 12 was dissolvedin a mixture of 30 ml of tetrahydrofuran with 5 ml of methanol and thenhydrogenated in the presence of palladium hydroxide-carbon under ahydrogen atmosphere of 3 kg/cm². After filtering off the catalyst anddistilling off the solvent under reduced pressure, the residue wasdissolved in 25 ml of di.methylformamide. After adding 4.5 ml (19.5mmol) of diphenylphosphoryl azide and 6.5 ml. (46.7 mmol) oftriethylamine, the mixture was stirred at room temperature for 4 days.Then it was concentrated and a saturated aqueous solution of ammoniumchloride was added thereto. Then it was extracted with ethyl acetate andwashed successively with a saturated aqueous solution of ammoniumchloride and a saturated aqueous solution of sodium chloride. Afterdrying over magnesium sulfate and concentrating, the residue waspurified by silica gel column chromatography. Thus 1.53 g of the titlecompound was obtained.

¹ H-NMR(DMSO-d₆) δ (ppm): 5.22(2H, br s), 6.27(1H, dd, J=8.0, 1.2 Hz),6.43(1H, dd, J=8.8, 1.2 Hz), 6.67(1H, t, J=8.0 Hz), 6.82(1H, br s),7.16-7.27(2H, m), 7.35(1H, dd, J=9.6, 3.2 Hz), 9.88(1H, br s)

Example 1

4-Methoxy-N-(10H-phenothiazin-1-yl)benenesulfonamide ##STR36##

107 mg (0.5 mmol) of 1-amino-10H-phenothiazine was dissolved in 4 ml ofpyridine. Then 2 ml of a solution of 115 mg (0.55 mmol) of4-methoxybenzene-sulfonyl chloride in tetrahydrofuran was added theretounder stirring at room temperature. After stirring at room temperatureovernight, the reaction mixture was concentrated. Then ethyl acetate andwater were added to the residue and the organic layer was scparated,washed with water and dried over magnesium sulfate. After concentrating,the residue was purified by silica gel column chromatography andrecrystallized from ethanol. Thus 115 mg of the title compound wasobtained.

M.p.: 158°-160° C. ¹ H-NMR(DMSO-d₆) δ (ppm): 3.74(3H, s), 6.60(1H, dd,J=8.0, 1.6 Hz), 6.65(1H, t, J=8.0 Hz), 6.70(1H, dd, J=8.0, 1.2 Hz),6.77-6.84(2H, m), 6.93(1H, dd, J=7.6, 1.2 Hz), 6.96-7.02(3H, m),7.57(2H, d, J=8.8 Hz), 7.62(1H, br s), 9.39(1H, br s)

Example 2

N-(9H-Carbazol-1-yl)-4-methoxybenzenesulfornamide ##STR37##

The title compound was obtained by a method similar to the one describedin Example 1.

M.p.: 201°-202° C.

Example 3

N-(9,10-Dihydroacridin-4-yl)-4-metboxybenzene-sulfonamide ##STR38##

The title compound was obtained by a method similar to the one describedin Example 1.

¹ H-NMR(DMSO-d₆) δ (ppm): 3.71(3H, s), 3.87(2H, s), 6.58-6.65(2H, m),6.74-6.80(2H, m), 6.88-6.92(1H, m), 6.94-7.04(4H, m), 7.57(2H, d, J=8.8Hz), 7.62(1H, br s), 9.29(1H, br s)

Example 4

N-(9(10H)-Acridinon-4-yl)-4-methoxyhenzenesulfonamide ##STR39##

The title compound was obtained by a method similar to the one describedin Example 1.

¹ H-NMR(DMSO-d6) δ (ppm): 3.75(3H, s), 7.02(2H, d, J=8.8 Hz),7.05-7.15(2H, m), 7.24-7.32(1H, m), 7.62(2H, d, J=8.8 Hz), 7.70-7.77(1H,m), 7.84(1H, d, J=8.0 Hz), 8.07-8.13(1H, m), 8.19(1H, dd, J=8.0, 1.2Hz), 9.74(1H, br s), 10.79(1H, br s)

Example 5

4-Methoxy-N-(10H-phenoxazin-1-yl)benzenesulfonamide ##STR40##

The title compound was obtained by a method similar to the one describedin Example 1.

M.p.: 220°-223° C. (decomp.).

Example 6

N-(10,11-Dihydro-5H-dibenz(b,f)azepin-4-yl)-4-methoxybenzenesulfonamide##STR41##

The title compound was obtained by a method similar to the one describedin Example 1.

M.p.: 182.5°-184.5° C.

¹ H-NMR(DMSO-d₆) δ (ppm): 2.78-2.92(4H, m), 3.64(3H, s), 6.56-6.70(4H,m), 6.82(2H, d, J=8.8 Hz), 6.88-6.95(2H, m), 6.97-7.03(1H, m), 7.26(1H,br s), 7.44(2H, d, J=8.8 Hz), 9.47(1H, br s)

Example 7

N-(7-Methoxy-9(10H)-acridinon-4-yl)-4-methoxybenzene-sulfonamide##STR42##

The title compound was obtained by a method similar to the one describedin Example 1.

M.p.: 253°-256° C. (decomp.).

¹ H-NMR(DMSO-d₆) δ (ppm): 3.76(3H, s), 3.86(3H, s), 7.00-7.08(4H, m),7.42(1H, dd, J=8.8, 3.2 Hz), 7.58(1H, d, J=3.2 Hz), 7.62(2H, d, J=8.8Hz), 7.86(1H, d, J=8.8 Hz), 8.10(1H, dd, J=7.6, 2.0 Hz), 9.72(1H, br s),10.84(1H, br s)

Example 8

4-Methoxy-N-(7-methoxy-10H-(-phenothiazin-1-yl)benzene-sulfonamide##STR43##

The title compound was obtained by a method similar to the one describedin Example 1.

M.p.: 157°-160° C.

Example 9

N-(5H-Dibenz b,f!azepin-4-yl)-4-methoxybenzene-sulfonamilde ##STR44##

The title compound was obtained by a method similar to the one describedin Example 1.

¹ H-NMR(DMSO-d₆) δ (ppm): 3.78(3H, s), 6.13-6.24(2H, m), 6.33-6.41(3H,m), 6.55(1H, t, J=7.6 Hz), 6.65-6.82(3H, m), 6.93-6.99(1H, m), 7.03(2H,d, J=8.8 Hz), 7.59(2H, d, J=8.8 Hz), 9.38(1H, br s)

Example 10

4-Methoxy-N-(6(5H)-phenanthridinon-4-yl)henzene-sulfonamide ##STR45##

The title compound was obtained by a method similar to the one describedin Example 1.

¹ H-NMR(DMSO-d₆) δ (ppm): 3.73(3H, s), 6.99(2H, d, J=8.8 Hz), 7.08(1H,d, J=7.6 Hz), 7.16(1H, t, J=7.6 Hz), 7.58(2H, d, J=8.8 Hz), 7.65(1H, t,J=7.6 Hz), 7.85(1H, t, J=7.6 Hz), 8.20-8.35(2H, m), 8.49(1H, d, J=8.4Hz), 9.80(1H, br s), 10.20(1H, br s)

Example 11

N-(7-Fluoro-10H-phernotbiazin-1-yl)-4-methoxy-benzenesulfonamide##STR46##

The title compound was obtained by a method similar to the one describedin Example 1.

M.p.: 166°-168° C.

Example 12

N-(Dibenrz(b,f)(1,4)oxazepin-11(10H)-on-9-yl)-4-methoxybenzenelfonamide##STR47##

The title compound was obtained by a method similar to the one describedin Example 1.

M.p.: 239.5°-241° C.

Example 13

N-(7-Hydroxy-10H-phenothiazin-1-yl)-4-methylbenzene-sulfonamide##STR48##

The title compound was obtained by a method similar to the one describedin Example 1.

¹ H-NMR(DMSO-d₆) δ (ppm): 3.73(3H, s), 6.36(1H, d, J=2.8 Hz), 6.41(1H,dd, J=8.4, 2.8 Hz), 6.52(1H, d, J=8.4 Hz), 6.58(1H, dd, J=6.4, 2.8 Hz),6.60(1H, t, J=6.4 Hz), 6.80(1H, dd, J=6.4, 2.8 Hz), 6.98(2H, d, J=8.8Hz), 7.30(1H, br s), 7.55(2H, d, J=8.8 Hz), 9.08(1H, br s), 9.38(1H, brs)

Example 14

N-(4-Acridinyl)-4-methoxybenzenesulfonamide ##STR49##

The title compound was obtained by a method similar to the one describedin Example 1.

M.p.: 143°-145° C.

Example 15

4-Methoxy-N-(10H-pyrido(3,2-b)(1,4)benzoxazin-9-yl)-benzenesulfonamide##STR50##

The title compound was obtained by a method similar to the one describedin Example 1.

¹ H-NMR(DMSO-d₆) δ (ppm): 3.77(3H, s), 6.51-6.60(3H, m), 6.63(1H, dd,J=7.6, 5.2 Hz), 6.92(1H, dd, J=7.6, 1.2 Hz), 7.05(2H, d, J=9.2 Hz),7.57(1H, dd, J=5.2, 1.2 Hz), 7.63(2H, d, J=9.2 Hz), 7.82(1H, br s),9.37(1H, br s)

Example 16

4-Methoxy-N-(5H-pyrido(2,3-b)(1,4)benzoxazin-6-yl)-benzenesulfonamide##STR51##

The title compound was obtained by a method similar to the one describedin Example 1.

¹ H-NMR(DMSO-d₆) δ (ppm): 3.80(3H, s), 6.16(1H, d, J=8.0 Hz), 6.43(1H,t, J=8.0 Hz), 6.56(1H, d, J=8.0 Hz), 6.78(1H, dd, J=7.6, 5.2 Hz),7.00(1H, dd, J=7.6, 1.6 Hz), 7.07(2H, d, J=8.8 Hz), 7.39(1H, dd, J=5.2,1.6 Hz), 7.65(2H, d, J=8.8 Hz), 7.82(1H, br s), 9.15(1H, br s)

Example 17

N-(5,11-Dihydrpdibenz(b,e)(1,4)oxazepin-6-yl)-4-methoxybenzenesulfonamide##STR52##

The title compound was obtained by a method similar to the one describedin Example 1.

M.p.: 153.5°-155° C.

¹ H-NMR(DMSO-d₆) δ (ppm): 3.65(3H, s), 4.83(2H, s), 6.53-6.59(2H, m),6.73(1H, t, J=7.6 Hz), 6.77(1H, d, J=7.6 Hz), 6.81(1H, dd, J=7.0, 3.7Hz), 6.91(2H, d, J=8.8 Hz), 7.04(1H, d, J=7.6 Hz), 7.15(1H, t, J=7.6Hz), 7.34(1H, br s), 7.53(2H, d, J=8.8 Hz), 9.48(1H, br s)

Example 18

4-Methoxy-N-(10H-phenothiazin-1-yl)henzenesulfonamide S-oxide ##STR53##

200 mg (0.516 mmol) of the compound of Example 1 was dissolved in 20 mlof dichloromethane and 111 mg (0.645 mmol) of m-chloroperbenzoic acidwas added thereto under ice-cooling and stirring. After stirring for 30minutes, the crystals thus precipitated were collected by filtration andrecrystallized from methanol-ethyl ether-dichloro-methane. Thus 150 mgof the title compound was obtained.

M.p.: 221°-223° C. (decomp.).

Example 19

4-Metboxy-N-(10H-phenothiazin-1-yl)benzenesulfonaimide S,S-dioxide##STR54##

210 mg (0.56 mmol) of the compound of Example 1 was dissolved in 20 mlof dichloromethane and 242 mg (1.40 mmol) of m-chloroperbenzoic acid wasadded thereto under ice-cooling and stirring. After stirring at roomtemperature for 12 hours, the crystals thus precipitated were collectedby filtration and recrystallized from ethanol. Thus 170 mg of the titlecompound was obtained.

M.p.: 247°-249° C.

Example 20

N-(7-Hydroxy-9(10H)-acridinon-4-yl)-4-methoxybenzene-sulfonamide##STR55##

0.47 g (1.5 mmol) of the compound of the Production Example 1 wasdissolved in a mixture of 50 ml of methanol with 150 ml of ethylacetate. After adding 50 mg of platinum oxide, hydrogenation waseffected at room temperature under atmospheric pressure. After filteringoff the formed insoluble matters, the mixture was concentrated todryness to thereby give 5-amino-2-benzyloxy-9(10H)-acridinone. Thisproduct was dissolved in 20 ml of pyridine and 5 ml of a solution of0.32 g (1.5 mmol) of 4-methoxy-benzenesulfonyl chloride intetrahydrofuran was added thereto under stirring at room temperature.After stirring for 1 hour, the reaction mixture was poured into asaturated aqueous solution of sodium chloride and extracted with ethylacetate. After concentrating, the residue was purified by silica gelcolumn chromatography. TheN-(7-benzyloxy-9-(10H)-acridinon-4-yl)-4-methoxybenzenesulfonamide thusobtained was dissolved in a mixture of 100 ml of methanol with 100 ml ofethyl acetate. After adding palladium-carbon, hydrogenation was effectedat room temperature under atmospheric pressure. After filtering off thepalladium-carbon and concentrating to dryness, 0.21 g of the titlecompound was obtained.

¹ H-NMR(DMSO-d₆) δ (ppm): 3.74(3H, s), 6.96-7.03(4H, m), 7.24(1H, dd,J=8.8, 2.8 Hz), 7.48(1H, d, J=2.8 Hz), 7.61(2H, d, J=8.8 Hz), 7.74(1H,d, J=8.8 Hz), 7.98(1H, d, J=7.6 Hz), 9.61(1H, br s), 10.63(1H, br s)

Example 21

N-(6-Hvdroxy-9(10H)-acridinon-4-yl)-4-methoxybenzene-sulfonamide##STR56##

The title compound was obtained by a method similar to the one describedin Example 20.

¹ H-NMR(DMSO-d₆) δ (ppm): 3.73(3H, s), 6.72(1H, dd, J=8.8, 2.0 Hz),6.96-7.07(5H, m), 7.59(2H, d, J=8.8 Hz), 8.00(2H, d, J=8.8 Hz), 9.71(1H,br s), 10.47(1H, br s), 10.49(1H, br s)

Example 22

N-(7-Hvdroxy-10H-phenoxain-1-yl)-4-methoxybenzene-sulfonamide ##STR57##

1.15 g (3.2 mmol) of the compound of Production Example 5 was dissolvedin 30 ml of tetrahydrofuran. After adding palladium-carbon thereto,hydrogenation was effected at room temperature under atmosphericpressure. Then the palladium-carbon was filtered off and the solutionwas concentrated to approximately halve the volume. After adding 5 ml ofpyridine and 0.72 g (3.5 mmol) of 4-methoxybenzenesulfonyl chloridethereto, the obtained mixture was stirred at room temperature overnight.Then ethyl acetate and water were added and the organic layer wasseparated, washed with water, dried over magnesium sulfate andconcentrated. Then the residue was purified by silica gel columnchromatography to thereby give 1.5 g of N-7-(tert-butyldimethylsilyloxy)-10H-phenoxazin-1-yl!-4-methoxybenzenesulfonamide.0.5 g (1 mmol) of this compound was dissolved in 10 ml oftetrahydrofuran and 1.2 ml of a 1M solution of tetra-n-butylammoniumfluoride in hexane was added thereto in a nitrogen atmosphere. Afterstirring at room temperature for 10 minutes, 1.5 ml of 1N hydrochloricacid and ethyl acetate were added to the reaction mixture. The organiclayer was washed with water, dried over magnesium sulfate andconcentrated to dryness. Thus 0.26 g of the title compound was obtained.

¹ H-NMR(DMSO-d₆) δ (ppm): 3.79(3H, s), 6.09(1H, d, J=2.4 Hz), 6.17(1H,dd, J=8.4, 2.4 Hz), 6.27(1H, dd, J=8.0, 1.6 Hz), 6.37(1H, t, J=8.0 Hz),6.45(1H, d, J=8.4 Hz), 6.45(1H, dd, J=8.0, 1.6 Hz), 7.06(2H, d, J=8.8Hz), 7.06(1H, br s), 7.65(2H, d, J=8.8 Hz), 8.97(1H, br s), 9.10(1H, brs)

Example 23

N-(9H-(Carbazol-1-yl-3-chlorobenzenesulfonamide ##STR58##

The title compound was obtained by a method similar to the one describedin Example 1.

M.p.: 162.5°-163.5° C.

Example 24

4-Methoxy-N-(3H-phenoxazin-3-on-9-yl)benzene-sulfonamide ##STR59##

0.12 g (0.51 mmol) of the compound of Production Example 4 was dissolvedin 20 ml of tetrahydrofuran. After adding palladium-carbon thereto,hydrogenation was effected at room temperature under atmosphericpressure. Then the palladium-carbon was filtered off and the solutionwas concentrated to approximately halve the volume. After adding 3 ml ofpyridine and 0.12 g (0.56 mmol) of 4-methoxybenzenesulfonyl chloridethereto, the obtained mixture was stirred at room temperature overnight.After concentrating, the residue was purified by silica gel columnchromatography. Thus 35 mg of the title compound was obtained.

¹ H-NMR(CDCl₃) δ (ppm): 3.82(3H, s), 6.31(1H, d, J=2.0 Hz), 6.87(1H, dd,J=10.0, 2.0 Hz), 6.92(2H, d, J=8.8 Hz), 6.93(1H, dd, J=8.4, 1.2 Hz),7.40(1H, d, J=10.0 Hz), 7.42(1H, t, J=8.4 Hz), 7.48(1H, dd, J=8.4, 1.2Hz), 7.86(2H, d, J=8.8 Hz), 8.43(1H, br s)

Example 25

4-Methoxy-N-(3-phenothiazin-3-on-9-yl)benzene-sulfonamide ##STR60##

The title compound was obtained as a by-product of the synthesis of thecompound of Example 13 from 4-methoxybcnzenesulfonyl chloride and1-amino-7-hydroxy-10H-phenothiazine.

¹ H-NMR(DMSO-d₆) δ (ppm): 3.72(3H, s), 6.85(1H, d, J=2.0Hz), 6.89(1H,dd, J=10.0, 2.0 Hz), 7.01(2H, d, J=8.8 Hz), 7.34-7.37(1H, m),7.43-7.50(2H, m), 7.78(1H, d, J=10.0 Hz), 7.80(2H, d, J=8.8 Hz),10.23(1H, br s)

Example 26

N-(5,11-Dihydrobenzo(b,e)(1,4)thiazepin-6-yl)-4-metboxybenzenesulfonamide##STR61##

The title compound was obtained by a method similar to the one describedin Example 1.

M.p.: 200°-202° C.

Example 27

N-(5,10-Dihydro-2-ftioro-11H-dibenzo(b,e)(1,4)-diazepin-11-on-6-yl)-4-methoxybenzenesulfonramide##STR62##

The title compound was obtained by reacting 4-methoxybenzenesulfonylchloride with the compound of Production Example 13 in the same manneras that of Example 1.

M.p.: 241.5°-243° C.

¹ H-NMR(DMSO-d₆) δ (ppm): 3.74(3H, s), 6.52(1H, dd, J=8.0, 1.2 Hz),6.76(1H, dd, J=8.8, 4.8 Hz), 6.79(1H, t, J=8.0 Hz), 6.86(1H, dd, J=8.0,1.2 Hz), 6.94(2H, d, J=8.8 Hz), 7.14(1H, td, J=8.8, 3.2 Hz), 7.14(1H,s), 7.32(1H, dd, J=9.6, 3.2 Hz), 7.47(2H, d, J=8.8 Hz), 9.54(1H, br s),10.06(1H, s)

Example 28

N-(7,8-Difluoro-10-pbenothiazin-1-yl)-4-methoxy-benenesulfonamide##STR63##

The title compound was obtained by a method similar to the one describedin Example 1.

M.p.: 158°-160° C. (decomp.). ¹ H-NMR(DMSO-d₆) δ (ppm): 3.76(3H, s),6.54(1H, dd, J=8.0, 1.2 Hz), 6.70(1H, t, J=8.0 Hz), 6.85(1H, dd, J=12.4,7.2 Hz), 6.89(1H, dd, J=8.0, 1.2 Hz), 7.01(2H, d, J=9.2 Hz), 7.17(1H,dd, J=10.4, 8.0 Hz), 7.55(2H, d, J=9.2 Hz), 7.88(1H, br s), 9.27(1H, brs)

Example 29

4-Methoxy-N-(10-methyl-10H-phenoxazin-1-yl)benzene-sulfonamide ##STR64##

The title compound was obtained by a method similar to the one describedin Example 1.

M.p.: 151°-153° C. ¹ H-NMR(DMSO-d₆) δ (ppm): 3.27(3H, s), 3.80(3H, s),6.22(1H, dd, J=8.0, 1.6 Hz), 6.58(1H, t, J=8.0 Hz), 6.66(1H, dd, J=8.0,1.6 Hz), 6.69(1H, dd, J=8.0, 1.6 Hz), 6.75(1H, dd, J=8.0, 1.6 Hz),6.79(1H, td, Jt=7.8, Jd=1.6 Hz), 6.93(1H, td, Jt=8.0, Jd=1.6 Hz),7.04(2H, d, J=8.8 Hz), 7.59(2H, d, J=8.8 Hz), 9.37(1H, br s)

Example 30

N-(5,11-Dibydro-2-bydroxydihenz(b,e)(1,4)oxazepin-6-yl)-4-methoxybenzensulfonamide##STR65##

Starting with2-(tert-butyldimethylsilyloxy)-5,11-dihydro-6-nitrodibenz(b,e)(1,4)oxazepine,which had been synthesized in the same manner as the one of ProductionExample 6, the title compound was obtained by a method similar to theone of Example 22.

M.p.: 200°-202° C. ¹ H-NMR(DMSO-d₆) δ (ppm): 3.71(3H, s), 4.78(2H, s),6.45(2H, d, J=4.8 Hz), 6.50(1H, s), 6.60(2H, s), 6.73(1H, t, J=4.8 Hz),6.95(2H, d, J=8.8 Hz), 6.99(1H, br s), 7.55(2H, d, J=8.8 Hz), 8.96(1H,br s), 9.42(1H, br s)

Example 31

N-10,11-Dihydro-2-methyl-5H-dihenzn(b,e)(1,4)-diazepin-6-yl)-4-methoxyhenenesulfonamide##STR66##

0.6 g (1.56 mmol) of the compound of Production Example 11 was dissolvedin 30 ml of methanol and 70 mg of paraformaldehyde and 2.35 ml of 1Nhydrochloric acid were added thereto. After heating under reflux for 30minutes and adding ethyl acetate, the reaction mixture was washed withwater and dried over magnesium sulfate. After concentrating, the residuewas crystallized from ethyl acetate-n-hexane. Thus 0.5 g of the titlecompound was obtained.

M.p.: 187°-192° C. (gradually melting). ¹ H-MMR(DMSO-d₆) δ (ppm):2.17(3H, s), 3.71(3H, s), 3.95(2H, br), 5.70(1H, br), 6.14(1H, d, J=8.0Hz), 6.37(1H, t, J=8.0 Hz), 6.56(1H, d, J=8.0 Hz), 6.58(1H, d, J=8.0Hz), 6.76(1H, d, J=2.0 Hz), 6.86(1H, dd, J=8.0, 2.0 Hz), 6.95(2H, d,J=8.8 Hz), 6.97(1H, br s), 7.56(2H, d, J=8.8 Hz), 9.34(1H, br s)

Example 32

N-(10,11-Dihydro-2-fluoro-5dibenzo(b,e)(1,4)-diazepin-6-yl)-4-methoxybenzenesulfonamide ##STR67##

To 40 ml of a suspension of 460 mg (12.1 mmol) of lithium aluminumhydride in tetrahydrofuran was added 500 mg (1.2 mmol) of the compoundof Example 27. After stirring at room temperature for 23 hours, ethylacetate was added thereto in portions under ice-cooling. Then an aqueoussolution of ammonium chloride was added thereto. After filtering off theformed insoluble matters, the filtrate was concentrated and an aqueoussolution of ammonium chloride and ethyl acetate were added thereto. Theorganic layer was separated, washed with water, dried over magnesiumsulfate and concentrated. Then the residue was purified by silica gelcolumn chromatography and recrystallized from ethanol. Thus 315 mg ofthe title compound was obtained.

The title compound could be obtained also by the same synthesis route asthe one of Example 31.

M.p.: 180°-181° C.

¹ H-MMR(DMSO-d₆) δ (ppm): 3.71(3H, s), 3.97(2H, br d, J=3.2 Hz),5.76(1H,1, br t, J=3.2 Hz), 6.20(1H, dd, J=8.0, 1.6 Hz), 6.41(1H, t,J=8.0 Hz), 6.59(1H, dd, J=8.0, 1.6 Hz), 6.67(1H, dd, J=8.8, 5.2 Hz),6.84-6.91(2H, m), 6.93(2H, d, J=8.8 Hz), 7.03(1H, br s), 7.54(2H, d,J=8.8 Hz), 9.34(1H, br s)

57 mg of the title compound was dissolved in a mixture of 3 ml ofmethanol and 6 ml of ethanol, then 1.4 ml of 1N hydrochloric acid wasadded thereto. After concentrating, ethanol was added and the crystalsthus precipitated were separated by filtration and recrystallized fromethanol. Thus 23 mg of the hydrochloride of the title compound wasobtained.

M.p.: 141.5°-143° C. (decomp.).

¹ H-MMR(DMSO-d₆) δ (ppm): 3.62(3H, s), 4.27(2H, s), 6.76-6.85(1H, m),6.82(2H, d, J=8.8 Hz), 6.85-6.94(2H, m), 6.97-7.08(2H, m), 7.29(1H, brs), 7.43(2H, d, J=8.8 Hz), 7.93(1H, br s), 9.92(1H, br s)

Example 33

N-(7-Hydroxymethyl-10-phenoxazin-1-yl)-4-methoxy-benzenesulfonamide##STR68##

Starting with7-((tert-butyldimethylsilyloxy)-methyl)-1-nitro-10H-phenoxazine, thetitle compound was obtained by a method similar to that of Example 22.

M.p.: 230°-232.5° C. ¹ H-MMR(DMSO-d₆) δ (ppm): 3.78(3H, s), 4.26(2H, d,J=5.6 Hz), 5.00(1H, t, J=5.6 Hz), 6.27(1H, dd, J=8.0, 2.4 Hz), 6.39(1H,t, J=8.0 Hz), 6.45(1H, br d, J=8.0 Hz), 6.54(1H, d, J=1.2 Hz), 6.57(1H,t, J=8.0 Hz), 6.67(1H, dd, J=8.0, 1.2 Hz), 7.05(2H, d, J=8.8 Hz),7.34(1H, br s), 7.65(2H, d, J=8.8 Hz), 9.12(1, br)

Example 34

4-Amino-N-(10-phenothiazin-1-yl)benzenesulfonamide ##STR69##

4-Nitrobenzenesulfonyl chloride was reacted with1-amino-10H-phenothiazine in the same manner as the one of Example 11.The product thus obtained was hydrogenated in the presence ofpalladium-carbon at room temperature under atmospheric pressure. Thusthe title compound was obtained.

¹ H-MMR(DMSO-d₆) δ (ppm): 5.96(2H, br s), 6.49(2H, d, J=8.8 Hz),6.53(1H, dd, J=8.0, 1.6 Hz), 6.62(1H, t, J=8.0 Hz), 6.77-6.82(3H, m),6.93(1H, dd, J=7.6, 1.2 Hz), 7.01(1H, dt, J=7.6, 1.2 Hz), 7.29(2H, d,J=8.8 Hz), 7.58(1H, br s), 9.14(1H, br s)

Example 35

4-Melthoxy-N-(5H-pyrimido(4,5-b)(1,4)benzothizin-6-yl)benzenesulfonamide##STR70##

The title compound was obtained by a method similar to the one describedin Example 1.

¹ H-MMR(DMSO-d₆) δ (ppm): 3.75(3H, s), 6.43(1H, br d, J=7.6 Hz),6.63(1H, br t, J=7.6 Hz), 6.81(1H, br d, J=7.6 Hz), 7.02(2H, d, J=9.2Hz), 7.56(2H, d, J=9.2 Hz), 7.92(1H, br s), 7.94(1H, br s), 8.30(1H, brs), 9.28(1H, br s)

Example 36

4-Methoxy-N-(5H-pyridor(3,4-b)(1,4)benzothiazine-4-yl)benzenesulfonamide##STR71##

The title compound was obtained by a method similar to the one describedin Example 1.

¹ H-MMR(DMSO-d₆) δ (ppm): 3.73(3H, s), 6.80(11H, dd, J=7.6, 1.2 Hz),6.84(1H, td, J=7.6, 1.2 Hz), 6.93(1H, dd, J=7.6, 1.2 Hz), 7.00(1H, td,J=7.6, 1.2 Hz), 7.00(2H, d, J=9.2 Hz), 7.46(1H, s), 7.59(2H, d, J=9.2Hz), 7.72(1H, s), 8.20(1H, s)

Example 37

N-(10-Acetyl-10,11-dihydro-5H-dihenzo(b,e)(1,4)-diazepin-6-yl)-4-methoxyhenzenesulfonamide##STR72##

N-(10,11-Dihydro-5H-dibenzo(b,e)(1,4)diazepin-6-yl)-4-methoxybenzensulfonamide,which had been synthesized in the same manner as the one of Example 31,was reacted with acetic anhydride at room temperature. Then the obtainedproduct was purified by silica gel column chromatography and thus thetitle compound was obtained.

¹ H-MMR(DMSO-d₆) δ (ppm): 1.74(3H, s), 3.54(3H, s), 3.68(1H, d, J=14.8Hz), 5.14(1H, d, J=14.8 Hz), 6.65-6.68(2H, m), 6.78(2H, d, J=9.2 Hz),6.81(1H, t, J=8.0Hz), 6.96-7.06(3H, m), 7.16(1H, dd, J=8.0, 1.2 Hz),7.37(1H, s), 7.40(2H, d, J=9.2 Hz), 9.60(1H, br s)

Example 38

N-(5,11-Ditiydro-2-hydroxydihenz(b,e)(1,4)oxazepin-6-yl)-4-methylbenzenesulfonamide##STR73##

The title compound was obtained by a method similar to the one describedin Example 30.

M.p.: 180.5°-182° C. ¹ H-MMR(DMSO-d₆) δ (ppm): 2.24(3H, s), 4.78(2H, s),6.42-6.49(2H, m), 6.50(1H, d, J=1.6 Hz), 6.56(1H, d, J=8.8 Hz), 6.60(1H,dd, J=8.8, 1.6 Hz), 6.74(1H, dd, J=5.2, 4.4 Hz), 6.95(1H, br s),7.25(2H, d, J=8.0 Hz), 7.51(2H, d, J=8.0 Hz), 8.95(1H, br s), 9.50(1H,br s)

Example 39

N-(5,11-Dihydro-8-fluoro-2-hdroxydihenz(b,e)(1,4)-oxazepin-6-yl)-4-methoxybenrzenesilfonamide##STR74##

The title compound was obtained by a method similar to the one describedin Example 30.

M.p.: 201° to 210° C. (gradually melting). ¹ H-MMR(DMSO-d₆) δ (ppm):3.70(3H, s), 4.80(2H, s), 6.35(1H, dd, Jt=9.6, 2.8 Hz), 6.50(1H, s),6.59(2H, s), t 6.68(1H, dd, J=79.6, 2.8 Hz), 6.85(1H, br), 6.96(2H, d,J=8.8 Hz), 7.50(2H, d, J=8.8 Hz), 8.96(1H, br s), 9.60(1H, br s)

Example 40

N-(5,11-Dihydrodibenz(b,e)(1,4)oxalelpin-4-yl)-4-methoxybenzenesulfonamide##STR75##

The title compound was obtained by a method similar to the one describedin Example 1.

M.p.: 164.5°-166.5° C. ¹ H-MMR(DMSO-d₆) δ (ppm): 3.66(3H, s), 4.90(2H,s), 6.63(1H, td, Jt=7.2, Jd=1.2 Hz), 6.66(1H, t, J=7.6 Hz),6.74-6.89(6H, m), 7.04(1H, d, J=7.6 Hz), 7.28(1H, br s), 7.50(2H, d,J=8.8 Hz), 9.49(1H, br s)

Example 41

N-(10,11-Dihydro-10-ethyl-5H-dihenzo(b,e)(1,4)-diazepin-6-yl)-4-meltoxybenzenesulfonamnide##STR76##

The title compound was obtained by reducing the compound of Example 37with lithium aluminum hydride in accordance with a conventional method.¹ H-MMR(CDCl₃) δ (ppm): 1.14(3H, t, J=7.2 Hz), 3.03(2H, q, J=7.2 Hz),3.80(3H, s), 4.10(2H, s), 6.13(1H, br s), 6.18(1H, dd, J=8.0, 1.6 Hz),6.44(11H, t, J=8.0 Hz), 6.72-6.76(2H, m), 6.82(1H, dd, J=8.0, 1.6 Hz),6.88(2H, d, J=9.2 Hz), 6.97(1H, d, J=7.6 Hz), 7.11(1H, td, J=7.6, 1.6Hz), 7.20(1H, br s), 7.68(2H, d, J=9.21 Hz)

Example 42

N-(5,11-Dihydro-2-hydroxydihenz(b,e)(1,4)oxazepin-6-yl)-5-methyl-2-thiopbhenesulfonamide##STR77##

The title compound was obtained by a method similar to the one describedin Example 30.

M.p.: 184°-188° C. (gradually melting). ¹ H-MMR(DMSO-d₆) δ (ppm):2.32(3H, s), 4.82(2H, s), 6.46-6.54(2H, m), 6.58(1H, d, J=7.6 Hz),6.60-6.66(2H, m), 6.71(1H, d, J=3.6 Hz), 6.74(1H, br), 7.00(1H, br),7.15(1H, d, J=3.6 Hz), 8.94(1H, br s), 9.69(1H, br s)

Example 43

N-(2-Acetylamino-10,11-dibydro-5H-dibhenz(b,e)(1,4)-diazepin-6-yl)-4-methoxybenzenesulfonamide##STR78##

The title compound was obtained by a method similar to the one describedin Example 31.

¹ H-MMR(DMSO-d₆) δ (ppm): 1.98(3H, s), 3.72(3H, s), 3.94(2H, br d, J=2.8Hz), 5.71(1H, br s), 6.14(1H, dd, J=8.0, 1.2 Hz), 6.36(1H, t, J=8.0 Hz),6.56(1H, dd, J=8.0, 1.2 Hz), 8.59(1H, d, J=8.4 Hz), 6.95(2H, d, J=8.8Hz), 6.98(1H, br s), 7.18(1H, d, J=2.4 Hz), 7.21(1H, dd, J=8.4, 2.4 Hz),7.56(2H, d, J=8.8 Hz), 9.37(1H, br s), 9.67(1H, br s)

Example 44

N-(10,11-Dihydro-2-(3-hydroxypropyloxy)-5H-dibenzo-(b,e)(1,4)(diazepin-6-yl)4-metbhoxybenzenesulfonamide##STR79##

The title compound was obtained by a method similar to the one describedin Example 31.

¹ H-MMR(DMSO-d₆) δ (ppm): 1.79-1.85(2H, m), 3.54(2H, dt, J=6.4, 5.2 Hz),3.73(3H, s), 3.95(2H, t, J=6.4 Hz), 3.99(2H, br d, J=2.8 Hz), 4.53(1H,t, J=5.2 Hz), 5.68(1H, br s), 6.09(1H, dd, J=8.0, 1.2 Hz), 6.33(1H, t,J=8.0 Hz), 6.53(1H, dd, J=8.0, 1.2 Hz), 6.59(1H, d, J=8.8 Hz), 6.61(1H,d, J=3.2 Hz), 6.66(1H, dd, J=8.8, 3.2 Hz), 6.82(1H, br s), 6.97(2H, d,J=8.8 Hz), 7.56(2H, d, J=8.8 Hz), 9.31(1H, br s)

Example 45

N-(5,11-Dihydro-2-fluoro-1-hydroxydibenz(b,e)-(1,4)oxazepin-6-yl)-4-methoxybenzenesulfonamide##STR80##

The title compound was obtained by a method similar to the one describedin Example 30.

M.p.: 219°-232° C. (gradually melting). ¹ H-MMR(DMSO-d₆) δ (ppm):3.68(3H, s), 4.93(2H, s), 6.21(1H, dd, J=8.8, 4.0 Hz), 6.53(1H, dd,J=7.2, 2.4 Hz), 6.56(1H, t, J=7.2 Hz), 6.79(1H, dd, J=7.2, 2.4 Hz),6.91(2H, d, J=8.8 Hz), 6.94(1H, dd, J=10.4, 8.8 Hz), 7.15(1H, br s),7.50(2H, d, J=8.8 Hz), 9.45(1H, br s), 9.70(1H, br s)

Example 46

N-(4-Chloro-10,11-dihvdro-2-fluoro-1-hvdroxy-5-dibenzo(b,e)(1,4)diazepin-6-yl)-4-methoxybenzene-sulfonamide##STR81##

The title compound was obtained by a method similar to the one describedin Example 31.

¹ H-MMR(DMSO-d₆) δ (ppm): 3.81(3H, s), 4.20-4.22(21H, m), 5.85(1H, br),5.89(1H, br), 6.37(1H, br t, J=7.6 Hz), 6.58(1H, br), 7.07(2H, d, J=8.8Hz), 7.25(1H, d, J=10.0 Hz), 7.63(1H, br), 7.64(2H, d, J=8.8 Hz),9.43(1H, br s), 9.79(1H, br s)

Example 47

N-(10,11-Dihydro-2-fluoro-1-hydroxy-5H-dibenzo(b,e)-(1,4)diazepin-6-yl)-4-methoxybenzenesulfonamide##STR82##

The compound of Example 46 was hydrogenated in the presence ofpalladium-carbon at room temperature under atmospheric pressure. Afterpurifying by silica gel column chromatography and recrystallizing fromchloroform-isopropyl ether, the title compound was obtained.

M.p.: 190°-192° C. (decomp.). ¹ H-MMR (DMSO-d₆) δ (ppm): 3.72(3H, s),4.06-4.08(2H, m), 5.65(1H, br), 6.11-6.16(2H, m), 6.38(1H, t, J=7.6 Hz),6.54(1H, brd, J=7.6 Hz), 6.84(1H, dd, J=10.4, 8.8 Hz), 6.90(1H, br s),6.93(2H, d, J=8.8 Hz), 7.53(2H, d, J=8.8 Hz), 9.32(1H, br s), 9.39(1H,br s)

Example 48

N-(2-Cyano-10,11-dihydro-5H-dibenzo(b,e)(1,4)diazepin-6-yl)-4-methoxybenzenesulfonamide##STR83##

The title compound was obtained by a method similar to the one describedin Example 31.

M.p.: 105°-107° C.

¹ H-MMR(DMSO-d₆) δ (ppm) :3.64(3H, s), 3.40(2H, br d, J=2.8 Hz),5.93(1H, br s), 6.42(1H, dd, J=8.0, 1.6 Hz), 6.57(1H, t, J=8.0 Hz),6.68(1H, br), 6.76(1H, d, J=8.4 Hz), 6.85(2H, d, J=8.8 Hz), 7.38(1H, d,J=2.0 Hz), 7.41(1H, dd, J=8.4, 2.0 Hz), 7.48(2H, d, J=8.8 Hz), 7.7.6(1H,br s), 9.39(1H, br s)

Example 49

N-(10,11-Dihydro-8-fluoro-5H-dibenzo(b,e)(1,4)-diazepin-4-yl)-4-methoxybenzenesulfonamide##STR84##

Starting withN-(2-((2-amino-4-fluorophenyl)-amino)phenyl)-4-methoxybenzenesulfonamide,the title compound was obtained by a method similar to the one describedin Example 31.

¹ H-MMR(DMSO-d₆) δ (ppm): 3.71(3H, s), 4.09(2H, br d, j=3.6 Hz),5.87(1h, br t, J=3.6 Hz), 6.29-6.41(2H, m), 6.50(1H, dd, J=8.4, 6.4 Hz),6.53(1H, t, J=8.0 Hz), 6.69(1H, dd, J=8.0, 1.6 Hz), 6.87(1H, br s),6.90(1H, br s), 6.91(2H, d, J=9.2 Hz), 7.51(2H, d, J=9.2 Hz), 9.42(1H,br s)

We claim:
 1. A sulfonamide derivative or a sulfonic ester derivativerepresented by the following formula (I) or a pharmacologicallyacceptable salt thereof: ##STR85## wherein G represents a lower alkoxyphenyl having 1 or 2 substituents, said substituents each being selectedfrom the group consisting of a halogen atom, a linear or branched C₁ -C₆alkyl group, a linear or branched C₁ -C₆ alkoxy group, and an aminogroup optionally substituted bv linear or branched C₁ -C₆ alkyl groups;Lrepresents oxygen or --N(R¹)--, wherein R¹ represents hydrogen or loweralkyl; and M represents a tricyclic structure of the following formula(a) ##STR86## wherein rings A and B represent each an optionallysubstituted unsaturated 5- or 6-membered ring, wherein the substituentsare each selected from the group consisting of a halogen atom, a linearor branched C₁ -C₆ alkyl group optionally substituted by a hydroxygroup, a linear or branched C₁ -C₆ alkoxy group optionally substitutedby a hydroxy group, a hydroxy group, an amino group optionallysubstituted by linear or branched C₁ -C₆ alkyl groups optionally havinga hydroxy group, C₁ -C₄ acyl groups, a cyano group and an oxo group; Xrepresents --N (R²)--, wherein R² represents hydrogen or lower alkyl, or--NHCO--; and Y represents oxygen, --S(O)_(n) --, --C(R³)(R⁴)--,--C(O)--, --N(R⁵)--, --CH(R⁶)CH(R⁷)--, --C(R⁸)═C(R⁹)--, --N(R¹⁰)C(O)--,--C(O)N(R¹⁰)--, --N═C(R¹¹)--, --C(R¹¹)═N--, --OCH(R¹²)--, --CH(R¹²)O--,--S(O)_(n) CH(R¹³)--, --CH(R¹³)S(O)_(n) --, --N(R¹⁴)CH(R¹⁵)--, or--CH(R¹⁵)N(R¹⁴)--, wherein n represents 0, 1 or 2, R³, R⁴, R⁶, R⁷, R⁸and R⁹ are the same or different from one another and each representshydrogen or lower alkyl, R⁵, R¹⁰, R¹¹, R¹², R¹³ and R¹⁵ each representshydrogen or lower alkyl, and R¹⁴ represents hydrogen, lower alkyl orlower acyl provided that a combination wherein G is 4-methylphenyl or4-methoxycarbonylaminophenyl, X in the tricyclic structure (a) of M is--N(R²)-- and Y is oxygen or --S(O)_(n) --, wherein n is 0, is excludedtherefrom.
 2. A sulfonamide derivative or a pharmacologically acceptablesalt as set forth in claim 1 wherein L is NH.
 3. A sulfonamidederivative, a sulfonic ester derivative or a pharmacologicallyacceptable salt thereof as set forth in claim 1 wherein G is4-methoxyphenyl.
 4. A sulfonamide derivative or a pharmacologicallyacceptable salt thereof as set forth in claim 1 wherein G is4-methoxyphenyl, L is --NH--, and M is a tricyclic structure (a) whereinX is NH and rings A and B are each an optionally substituted aromatic6-membered ring.
 5. A sulfonamide derivative or a pharmacologicallyacceptable salt thereof as set forth in claim 4 wherein M is a tricyclicstructure (a) wherein the center ring having X and Y is a 7-memberedring.
 6. A process for producing a sulfonamide derivative, a sulfonicester derivative or a pharmacologically acceptable salt thereof as setforth in claim 1 characterized by reacting a sulfonic acid representedby the following general formula (II):

    Gb--SO.sub.3 H                                             (II)

wherein Gb represents optionally protected G as defined in claim 1;or areactive derivative thereof with a compound represented by the followinggeneral formula (III):

    H--L--Ma                                                   (III)

wherein L has the same meaning as the one defined in claim 1; and Marepresents optionally protected M as defined in claim 1;and removing theprotecting group(s), if any, of the product thus obtained, if desired.7. A process for producing a sulfonamide derivative or apharmacologically acceptable salt thereof as set forth in claim 1characterized by subjecting a compound represented by the followinggeneral formula (IV): ##STR87## wherein Gb, R¹ and R² have each the samemeaning as the one defined above;R^(14a) represents hydrogen or loweralkyl; and rings Aa and Ba represent respectively the rings A and B asdefined in claim 1 which are optionally protected;to intramolecular ringclosure by reacting with an aldehyde and removing the protectinggroup(s), if any, of the product thus obtained, if desired.
 8. A processfor producing a sulfonamide derivative or a pharmacologically acceptablesalt thereof as set forth in claim 1 characterized by subjecting acompound represented by the following general formula (V): ##STR88##wherein Gb, R¹, R², R¹⁴, R¹⁵ and rings Aa and Ba have each the samemeaning as the one defined above; andV represents a leaving group;tointramolecular ring closure and removing the protecting group(s), ifany, of the product thus obtained, if desired.
 9. A process forproducing a sulfonamide derivative or a pharmacologically acceptablesalt thereof as set forth in claim 1 characterized by reducing acompound represented by the following formula (VI): ##STR89## whereinGb, R¹, R² and rings Aa and Ba have each the same meaning as the onedefined above; andYa represents --NHCO-- or --N═C(R¹¹), wherein R¹¹represents hydrogen or lower alkyl;and removing the protecting group(s),if any, of the product thus obtained, if desired.
 10. A sulfonamidederivative, a sulfonic ester derivative or a pharmacologicallyacceptable salt thereof as set forth in claim 1 which is represented bythe following general formula (I-a): ##STR90## wherein R³¹ representshydrogen, halogen, lower alkyl, lower alkoxy, nitro, cyano or aminooptionally substituted by lower alkyl;R³² and R³³ are the same ordifferent from each other and each represents hydrogen, lower alkyl,lower alkoxy or halogen provided that at least one of R³¹, R³² or R³³ isa lower alkoxy; L represents --N(R³⁴)-- or oxygen, wherein R³⁴represents hydrogen or lower alkyl; and M represents a tricyclicstructure of the following formula (a): ##STR91## wherein rings A and Brepresent each an optionally substituted unsaturated 5- or 6-memberedring;X represents --N(R³⁵)--or --NHCO--; and Y represents oxygen,sulfur, --S(O)--, --S(O₂)--, --C(R³⁶)R(³⁷)--, --C(O)--, --N(R³⁸)--,--CH₂ CH₂ --, --CH═CH--, --NHCO--, --CONH--, --CH═N--, --N═CH═, --CH₂O--, --OCH₂ --, --CH₂ S--, --SCH₂ --, --CH₂ N(R³⁹)--, --N(R⁴⁰)CH₂ --,--CH₂ S(O)--, --S(O)CH₂ --, --CH₂ S(O₂)-- or --S(O₂)CH₂ --; ##STR92##wherein R³⁵, R³⁶, R³⁷, R³⁸, R³⁹, R⁴⁰, and R⁴¹ each represents hydrogenor lower alkyl.
 11. A medicinal composition comprising an effectiveanti-tumor amount of a sulfonamide derivative, a sulfonic ester or apharmacologically acceptable salt thereof as set forth in claim 1, and apharmacologically acceptable filler.
 12. A sulfonamide derivative orpharmaceutically acceptable salt thereof as set forth in claim 12 whichis represented by the following formula: ##STR93##
 13. A sulfonamidederivative or pharmaceutically acceptable salt thereof of claim 1,wherein L is --N(R¹)--.
 14. A sulfonamide derivative or sulfonic esterderivative or pharmaceutically acceptable salt thereof of claim 1,wherein A and B are each a benzene ring.
 15. A sulfonamide derivative orsulfonic ester derivative or pharmaceutically acceptable salt thereof ofclaim 1, wherein Y is --N(R¹⁴)CH(R¹⁵)--.
 16. A sulfonamide derivative orsulfonic ester derivative or pharmaceutically acceptable salt thereof ofclaim 1, wherein the substituents are each selected from the groupconsisting of a halogen, a lower alkyl, a lower alkoxy, and an aminogroup optionally substituted with a lower alkyl.
 17. A sulfonamidederivative or sulfonic ester derivative or pharmaceutically acceptablesalt thereof of claim 1, wherein A and B are each a benzene ring, and Yis --N(R¹⁴)CH(R¹⁵).
 18. A method of treating nasopharyngel cancer,pulmonary cancer, intestinal cancer, mammary cancer, uterus cancer,gastric cancer, ovarian cancer or liver cancer, comprising:administeringan effective anti-tumor amount of a sulfonamide derivative, a sulfonicester derivative or a pharmacologically acceptable salt thereof as setforth in claim 1 to a patient in need thereof.